Investigating a New Oral Combination for Relapsed/Refractory CLL and Richter Transformation

Finding effective treatment options for people living with relapsed or refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) or Richter transformation (a rare but aggressive complication of CLL) may be difficult. Many patients facing these diagnoses have already gone through several lines of therapy, highlighting the need for additional options. 

A recent clinical trial explored the combination of two oral medications—venetoclax and duvelisib—to determine their safety and effectiveness in treating these conditions.

The Advantages of Oral Treatments

Venetoclax (Venclexta), when used with rituximab (Rituxan), is an effective treatment for CLL but requires two years of therapy, including six months of rituximab intravenous infusions. Evaluating additional oral medications to pair with venetoclax could help improve a patient’s quality of life, as it is more convenient than an IV treatment. 

Duvelisib (Copiktra) is an oral medication for patients with relapsed or refractory CLL after two prior treatments. Although it has not been pulled from FDA approval as its side effects are clearly listed in the drug's warnings, an advisory committee to the FDA does not recommend its use for people with CLL due to its high risk profile. The reason for evaluating it in the clinical trial below, combined with venetoclax, came from the idea that the combination may be effective enough for the benefits to outweigh the risks. 

Discussing new treatment options with your healthcare team is essential. Clinical trials like this one help expand treatment possibilities and improve outcomes for patients. You can stay informed with HealthTree’s Clinical Trial Finder and use the different filters to discover personalized options.

If you are interested in additional relapsed/refractory treatment options for CLL/SLL, click here. 

A Clinical Trial with an All-Oral Combination

This phase 2 clinical trial included 38 patients with relapsed or refractory CLL/SLL or Richter transformation who received at least one prior treatment or no venetoclax treatment in the past year. 

The treatment plan involved:

• Duvelisib at 25 mg twice daily for seven days
• Adding venetoclax on day 8, beginning at a low dose and gradually increasing to 400 mg per day over several weeks
• Patients with Richter transformation could start venetoclax at a higher dose and reach 400 mg in five days
• After one year of treatment, patients with no detectable cancer cells in their bone marrow could stop therapy and restart if their disease returned
• Those with detectable cancer cells continued venetoclax alone and had the option to stop later if they achieved complete remission

Were Venetoclax + Duvelisib Effective?

Relapsed/Refractory CLL Results

• 97% of CLL patients responded to treatment 
• After 12 months, 72% of patients continued to respond to treatment, with 44% achieving a complete remission
• 68% remained progression-free after three years

Richter Transformation Results

• 30% of the patients with Richter transformation achieved a complete remission, including one who received a stem cell transplant and remained in remission for over two years.

Progression-free survival rates were lower for high-risk patients with specific genetic mutations (47%)  and those previously treated with BTK inhibitors (46%).

What Were the Side Effects of Venetoclax + Duvelisib? 

• The most common side effects were low blood cell counts, with 86% of patients having low white blood cell counts (neutropenia), and 58% of patients with low platelet counts (thrombocytopenia). 
• Other common side effects included diarrhea (63%), nausea (55%), liver enzyme changes, high blood pressure, and headaches.
• Serious side effects included colitis (inflammation of the large intestine), tumor lysis syndrome (a condition where cancer cells break down too quickly), infections, and febrile neutropenia (fever caused by having low white blood cells).
• Five patients had to discontinue because of the serious side effects that they were experiencing.

Conclusion

This study showed that an all-oral, time-limited treatment with venetoclax and duvelisib is effective for patients with relapsed or refractory CLL/SLL and Richter transformation, including those with high-risk disease. Side effects were common but considered manageable. These results support further research into this combination therapy for CLL/SLL and Richter transformation patients.

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Keep Reading CLL News

Source: 

• A Phase 2 Study of Duvelisib and Venetoclax in Patients with Relapsed or Refractory (R/R) Chronic Lymphocytic Leukemia (CLL) or Richter’s Syndrome (RS)